ArticleMolecular therapy : the journal of the American Society of Gene Therapy2022
Single AAV-mediated CRISPR-Nme2Cas9 efficiently reduces mutant hTTR expression in a transgenic mouse model of transthyretin amyloidosis.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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11 citing papers in PubMed, 24 citations in OpenAlex.
- Spatially concentrated adenine base editors efficiently correct PLP1 mutations in oligodendrocytes.Nucleic acids research · 2026Article
- The Promise and Pitfalls of AAV-Mediated Gene Therapy for Duchenne Muscular Dystrophy.Current issues in molecular biology · 2025Review
- Engineering a High-Fidelity MAD7 Variant with Enhanced Specificity for Precision Genome Editing via CcdB-Based Bacterial Screening.Biomolecules · 2025Article
- Nanoscale synthetic biology with innovative medicinal applications.Fundamental research · 2025Review
- Efficient and safe in vivo treatment of primary hyperoxaluria type 1 via LNP-CRISPR-Cas9-mediated glycolate oxidase disruption.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Therapeutic gene correction of HBB frameshift CD41-42 (-TCTT) deletion in human hematopoietic stem cells.Advanced biotechnology · 2025Article
- Expanding the CRISPR/Cas toolkit: applications in proteomics and theranostics.Frontiers in bioengineering and biotechnology · 2025Review
- Recent advances in therapeutic CRISPR-Cas9 genome editing: mechanisms and applications.Molecular biomedicine · 2023Review
- CRISPR/Cas9 therapeutics: progress and prospects.Signal transduction and targeted therapy · 2023Review
- Adenine Base EditingGEN biotechnology · 2022Article
- Self-inactivating, all-in-one AAV vectors for precision Cas9 genome editing via homology-directed repair in vivo.Nature communications · 2021Article
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Transthyretin (TTR) amyloidosis is a hereditary life-threatening disease characterized by deposition of amyloid fibrils. The main causes of TTR amyloidosis are mutations in the TTR gene that lead to the production of misfolded TTR protein. Reducing the production of toxic protein in the liver is a validated strategy to treat TTR amyloidosis. In this study, we established a humanized mouse model that expresses mutant human TTR (hTTR; V30M) protein in the liver to model TTR amyloidosis. Then, we compared the efficiency of reducing the expression of mutant hTTR by dual adeno-associated virus 8 (AAV8)-mediated split SpCas9 with that by single AAV8-mediated Nme2Cas9 in this model. With two gRNAs targeting different exons, dual AAV-mediated split SpCas9 system achieved efficiencies of 37% and 34% reduction of hTTR mRNA and reporter GFP expression, respectively, in the liver. Surprisingly, single AAV-mediated Nme2Cas9 treatment resulted in 65% and 71% reduction of hTTR mRNA and reporter GFP, respectively. No significant editing was identified in predicted off-target sites in the mouse and human genomes after Nme2Cas9 targeting. Thus, we provide proof of principle for using single AAV-mediated CRISPR-Nme2Cas9 to effectively reduce mutant hTTR expression in vivo, which may translate into gene therapy for TTR amyloidosis.
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